Various age-related chronic diseases have been linked to oxidative stress. The cellular antioxidant response pathway is regulated by the transcription factor Nrf2. Therefore, plant-derived Nrf2 activators might be useful therapeutics to stimulate the body's defense mechanisms. Our study was focused on the discovery of potent Nrf2 activators from medicinal plants. Initially, a variety of medicinal plant extracts were screened for Nrf2 activity using an Nrf2 luciferase reporter cell line. Among these, Valerian (V. officinalis) root was identified as a potent candidate. Sequential extraction and bioassay-guided fractionation led to the isolation of four Nrf2-active compounds, which were structurally identified by NMR and LC/HRMS as the known compounds isovaltrate, valtrate, jatamanvaltrate-P, and valerenic acid. These four compounds were then tested in relevant biological assays. Firstly, their effects on the expression of glutathione S-transferase (GST), glutamate—cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX), and heme oxygenase 1 (HO-1) were determined in HepG2 cells. GSTP1 and GCLC were upregulated by isovaltrate, valtrate and jatamanvaltrate-P, HO-1 by isovaltrate, jatamanvaltrate-P and valerenic acid. The four compounds also increased the levels of glutathione (GSH) and its metabolite, CysGly. As GSH aids in the detoxification of H2O2, cytoprotective effects of these four Nrf2 activators against H2O2 toxicity were investigated, and indeed, the compounds significantly improved cell survival. This study provides evidence that four valepotriates from the roots of V. officinalis are activators of Nrf2-mediated antioxidant and detoxification pathways. Our data might expand the medical use of this plant beyond its current application as a sleep aid.
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